The present invention generally relates to a novel family of biocompatible surfactant copolymers having a large spectrum of uses, notably in the pharmaceutical field, and for synthesizing materials in the dispersed state, as well as treating the surface of materials and biomaterials.
More particularly, the object of the present invention is surfactant biocompatible copolymers comprising one or more sequences having hydrophobic character which are constituted mainly of recurring units or non-recurring units of general formula defined below, in particular forming a poly(methylidene malonate).
Surfactant copolymers formed from one or more sequences having a hydrophilic character and one or more sequences having a hydrophobic character have been known for a long time.
In particular, the products constituted of polyoxyethylene sequences having hydrophilic character and polyoxypropylene sequences having hydrophobic character and marketed under the designation PLURONIC(copyright) are commonly used for preparing compositions for cosmetic or pharmaceutical use.
The main drawback of these copolymers comes from the fact that they comprise no biodegradable sequence.
Surfactant copolymers comprising biodegradable sequences have already been described for example in the EP 583 955 document. These are block copolymers which contain ethylene oxide units and units derived from amino acids, as hydrophobic sequences.
The biodegradability of these known copolymers is accompanied by a cleavage of the main chain.
It has been discovered, and this constitutes the basis of the present invention, a novel family of biocompatible surfactant copolymers which are biodegradable via a mechanism of bio-erosion which does not significantly modify the degree of polymerisation of said copolymer.
More specifically, the copolymers in accordance with the invention can degrade chemically or biochemically by cleavage of the lateral substituents constituting the sequences having hydrophobic character, and this bio-erosion is advantageously accompanied by the passage of a copolymer having the characteristics of a surfactant into an entirely hydrophilic copolymer of the same degree of polymerisation as the staring polymer.
The copolymers in accordance with the present invention have very many advantages over the surfactant copolymers known to date, these advantages result from the particular chemical structure of their sequences having hydrophobic character.
These sequences notably enable providing copolymers which have various structures, block structures or grafted structures, it being difficult for the latter structures to be accessible in the case of the copolymers described for example in the EP 583 955 document.
The high reactivity, in anionic polymerisation as well as in radical polymerisation, of the monomers used for preparing these sequences having hydrophobic character, facilitates adjusting the molecular masses of these sequences, and, consequently, the properties of the copolymers.
Finally, the copolymers in accordance with the present invention have, according to the chemical structure of their sequences having hydrophobic character, various degradation kinetics and are therefore suitable for a large range of applications.
Thus, according to a first aspect, the present application aims to cover biocompatible copolymers of the type comprising at least one sequence having a hydrophilic character and at least one sequence having a hydrophobic character, characterised in that said sequence having hydrophobic character is formed:
either from a homopolymer constituted of recurring units of the following general formula (I): 
xe2x80x83in which:
R1 represents an alkyl group having 1 to 6 carbon atoms or a (CH2)mxe2x80x94COOR3 group in which m is an integer between 1 and 5 and R3 represents an alkyl group having 1 to 6 carbon atoms;
R2 represents an alkyl group having 1 to 6 carbon atoms; and
n is an integer between 1 and 5;
or from a random copolymer constituted of different recurring units of formula (I) as defined above;
or, finally, from a random copolymer constituted mainly of units of formula (I) as defined above.
Advantageously, the above-mentioned sequence having hydrophobic character will be formed from a homopolymer constituted of recurring units of formula (I) as defined above.
Without leaving the context of the present invention, this sequence having hydrophobic character can also be formed from a random copolymer constituted of different recurring units of formula (I) as defined above, or even from a random copolymer constituted mainly of units of formula (I) as defined above, i.e. constituted of at least 50%, expressed in molar proportions, of such units, it being possible for the other units to be formed from malonic, vinylic, or acrylic monomers which are copolymerisable with the methylidene malonate units of formula (I).
According to a currently preferred embodiment of the invention, the above-mentioned sequence having hydrophobic character is constituted of recurring units of the above-mentioned general formula (I) in which:
R1 represents an alkyl group having 1 to 6 carbon atoms;
R2 represents an alkyl group having 1 to 6 carbon atoms; and
n is a number equal to 1.
According to a particularly preferred embodiment of the invention, the above-mentioned sequence having hydrophobic character is formed from a homopolymer constituted of recurring units of formula: 
According to a particular characteristic, the sequence having hydrophilic character of the biocompatible copolymers in accordance with the present invention is selected from a poly(oxyethylene), a poly(vinyl alcohol), a poly(vinylpyrrolidone), a poly(N-2 hydroxypropyl methacrylamide), a poly(hydroxyethyl methacrylate), a hydrophilic poly(amino acid) such as a polylysine, a polysaccharide, and will preferably be constituted of a poly(oxyethalene).
The copolymers in accordance with the present invention can have various structures, block structures or grafted structures.
These copolymers may generally be characterised:
by a content by weight of sequences having hydrophobic character of between 5 and 95%, preferably of between 10 and 90%;
by a total molar mass of the sequences having hydrophobic character between 1,000 and 80,000 g/mol, and preferably between 1,000 and 50,000 g/mol.
The copolymers in accordance with the present invention can be prepared by classical polymerisation techniques well known to the person skilled in the art.
Amongst these techniques, anionic polymerisation, radical polymerisation, or even the technique of coupling the precursor sequences of the copolymer, will preferably be used, these sequences having been adequately functionalised beforehand on the chain end.
The anionic polymerisation is more particularly suitable for preparing block copolymers.
The anionic copolymerisation comprises the sequential addition of the monomers and enables obtaining copolymers of perfectly defined structure, the amounts of initiators and monomers engaged enabling controlling the degree of polymerisation of each of the sequences.
Thus, a block copolymer can be obtained:
either by anionic polymerisation of a first monomer and reaction of the growing chain with a second monomer;
or by activation of a precursor polymer which will act as initiator for the polymerisation of a second monomer.
The initiator agents which can be used within the context of these anionic polymerisations will generally be:
on the one hand, organometallic derivatives, such as butyllithium, and diphenylhexyllithium in particular;
on the other hand, alkoxides, and in particular macromolecular alkoxides, such as a POE alkoxide, which can be generated by activation of a hydroxy function with the aid of cumylpotassium, diphenylmethylpotassium, or naphthalenepotassium.
The anionic polymerisation will generally be carried out in a solvent which is compatible with the various sequences of the copolymer.
In the case in which the sequence having hydrophilic character is constituted of a poly(oxyethylene) and the sequence having hydrophobic character is constituted of a poly(methylidene malonate), the block copolymers according to the invention will be prepared preferably by successive anionic polymerisation of the ethylene oxide and then of the methylidene malonate, or by activation of a commercial monohydroxylated polyoxyethylenated precursor and subsequent anionic polymerisation of the poly(methylidene malonate) sequence.
Generally, tetrahydrofuran will preferably be used as polymerisation solvent, this product enabling working in a homogeneous environment and favourably influencing the polymerisation kinetics.
As regards the starting monomers, it will be possible for the methylidene malonates to be prepared for example by following the method described in the EP 283 346 patent which corresponds to U.S. Pat. Nos. 4,931,584 and 5,142,098 patents, which are incorporated herein by reference, and the methylidene malonates will generally be degassed, under vacuum of a pallet pump, to constant weight in order to remove the polymerisation inhibitor (SO2).
The monomers used for preparing the hydrophilic sequences will generally be commercial products.
The coupling technique is also more particularly suitable for preparing block copolymers.
This reaction is generally carried out from pre-synthesised and functionalised homopolymers, in the presence of a coupling agents and optionally in the presence of an activating agent, in a suitable solvent.
An xcex1-carboxy group-functionalised poly(oxyethylene)homopolymer and an xcex1-hydroxy group-functionalised poly(methylidene malonate)homopolymer will advantageously be used in the case of the preparation of the preferred copolymers according to the invention, the hydrophilic sequence of which is constituted of a poly(oxyethylene) and the hydrophobic sequence of which is constituted of a poly(methylidene malonate).
The xcex1-carboxy group-functionalised poly(oxyethylene)homopolymer can be obtained for example by transforming a commercial xcex1-hydroxy group-functionalised poly(oxyethylene) with succinic anhydride.
The xcex1-hydroxy group-functionalised poly(methylidene malonate)homopolymer can be obtained directly by anionic synthesis in aqueous medium or by anionic synthesis in a solvent using an aqueous sodium hydroxide solution as polymerisation initiator.
Dicyclohexylcarbodiimide (DCCI) will advantageously be used as coupling agent which is particularly adapted to this polymerisation.
The coupling reaction can optionally be activated by basic catalysis, and will generally take place in a solvent which is compatible with the homopolymers, such as dichloromethane in the particular case of the preferred copolymers of the invention.
The radical polymerisation is more particularly suitable for preparing grafted copolymers.
This polymerisation is generally carried out from a macromonomer, i.e. an oligomer which bears, on one of its ends, an ethylenic group which is radical polymerisable and which is able to react with a monomer to form a copolymer having a grafted structure.
This polymerisation will generally be carried out in the presence of an initiator in a suitable solvent.
It will be possible for various functionalised macromonomers to be used in the case of the preparation of the preferred copolymers of the invention, the hydrophilic sequence of which is constituted of a poly(oxyethylene).
It will be more particularly preferred to use a methacryloyl group-functionalised poly(oxyethylene)macromonomer.
Such a product can be commercial (Aldrich) and will be constituted for example by a poly(oxyethylene) chain of molar mass between 308 and 440 g/mol, or will be prepared from a commercial poly(ethylene glycol)monomethylether by coupling with methacrylic acid in dichloromethane to form a methoxy terminal function.
Such a macromonomer may even be prepared by activation of a poly(oxyethylene) and subsequent reaction with methacryloyl chloride.
It is also be possible for the copolymers having grafted structures according to the invention to be prepared by transesterification of a poly(oxyethylene) monomethylether with the lateral ester chains of pre-synthesised poly(methylidene malonate).
This transesterification will generally be carried out with alcohol in the presence of a catalyst at high temperature.
In general, the copolymers in accordance with the present invention have a large range of applications as surfactants.
These copolymers enable in particular reducing the surface tension of water and the interfacial tension of a water/non-water-immiscible organic solvent system.
These copolymers even enable preparing micellar systems in aqueous media which are especially useful as vectors for active principles.
These copolymers also enable preparing or stabilising simple water-in-oil or oil-in-water type emulsions.
These copolymers even enable encapsulating various active substances, particularly substances of therapeutic use.
The copolymers in accordance with the present invention even find application as colloid protectors for stabilising nanoparticles.
They will be particularly useful when these particles are prepared from polymers comprising recurring units which are identical to those of their sequences having a hydrophobic character, and this facilitates, as is understood, the anchoring of the copolymer onto the surface of these particles while at the same time conferring a biocompatible and hydrophilic character to them by virtue of the presence in said copolymer of at least one biocompatible hydrophilic sequence.
The copolymers in accordance with the invention can also be used as agents for treating the surface of materials or biomaterials, particularly for conferring a hydrophilic character to the treated surfaces by anchoring of said copolymers, or for minimising the interfacial adhesion with animal tissues, cells or biomolecules, when these materials or biomaterials are susceptible in coming into contact with said cells or biomolecules.
The copolymers in accordance with the present invention can also be used for preparing particles which can be used as contrast agents.
The copolymers in accordance with the present invention can even be used as biocompatible materials, for example in the form of films or moulded pieces, as well as for treating the surface of implant structures, and for minimising or favouring interfacial adsorption mechanisms.